During the last year, we continued to define the molecular events that regulate hematopoietic stem and progenitor cell (HSPC) quiescence, survival, self-renewal and, myeloid cell lineage commitment and differentiation. We have focused our efforts on transcription factors since they are essential for stem cell growth and differentiation, and are frequently deregulated during the development of leukemias and lymphomas. We previously found that the helix loop helix (HLH) transcription factor, inhibitor of differentiation 1 (Id1), is induced during the early stages of myeloid development, and can instruct hematopoietic stem cells toward a myeloid versus erythroid and lymphoid cell fate suggesting that this gene and other family members Id2 and Id3 may regulate cell specification from HSPC. We have found that Id1-/- show impaired hematopoietic development including increased hematopoietic stem/progenitor cell cycling, and defects in B cell and myeloid cell development. We determined that the hematopoietic phenotype observed in the Id1-/- mice was not intrinsic to the Id1-/- hematopoietic cells, but was due to defects in the microenvironment or niche. We determined that loss of Id1 and Id3 were required to recapitulate this phenotype in mice on a pure C57BL/6 background. We found that mice that lack Id1 and Id3 (double knock out, dKO) show impaired hematopoietic development and show dilated and discontinuous bone marrow sinusoid endothelial cells (SECs). H & E stains show RBCs present in the intra femoral space, suggesting the SECs are leaky. We confirmed this phenotype in a mouse model that specifically deletes Id1/Id3 in endothelial cells (VE-Cad-ERCre transgenic mice). Future studies are aimed at determining the mechanism(s) by which loss of Id1/Id3 affect SEC integrity. In other studies, we discovered that mice that lacked Id1 show enhanced HSC self-renewal in serial bone marrow transplant assays. We found that the Id1-/- HSCs show reduced cell cycling and reduced levels of H2AX staining suggesting that the Id1-/- HSC show increased quiescence during BMT. We also found that the Id1-/- HSCs show reduced mitochondrial biogenesis, reduced ROS production and increased levels of reduced glutathione confirming that Id1-/- HSCs show increased quiescence after BMT. Additional studies demonstrate that Id1-/- HSCs show reduced proliferative response to cytokines in vitro. Id1 is induced in HSCs by cytokines in vitro and in vivo and promote HSC proliferation. Molecular analysis of Id1-/- HSCs demonstrate that they have a quiescent signature and confirm that they show reduced cycling, reduced mitochondrial biogenesis and oxidative phosphorylation, and ribosomal biogenesis. Further studies suggest that loss of Id1 leads to increased E protein activity and increased expression of cyclin dependent kinase inhibitors. Collectively, we provide evidence that Id1-/- HSCs are protected from proliferative exhaustion during BMT, chronic stress and aging. These studies were recently published in Cell Stem Cell, and have lead to current studies pursing novel methods and approaches to reduce Id1 expression in HSCs in vivo to protect HSCs from exhaustion during stress and aging. To identify novel transcriptional regulators of myeloid cell growth and differentiation, we have compared the global gene expression profile of undifferentiated and differentiating hematopoietic progenitor cells. We have identified a novel zinc finger transcription factor of unknown function, POGZ, which is down regulated during the early stages of myeloid development. We have discovered that fetal liver hematopoietic cell development is impaired in POGZ-/- mice, which includes a dramatic decrease in cellularity. We have found that loss of Pogz expression leads to a decrease in Bcl11a and KLF2 expression, and that embryonic globin genes are not silenced. We have found that fetal globin expression is not repressed in normal human bone marrow progenitors transduced with shRNA vectors that knock down Pogz expression, and that Bcl11a expression also decreases in this model. Thus, Pogz is required to repress human fetal globin expression, and suggests that reducing Pogz expression in patients with sickle cell disease and beta-thalassemia could have therapeutic potential. These studies were published in Cell Reports 2018, and future collaborative studies are focused on understanding how Pogz regulated human fetal globin expression.